EP0259782B1 - Dérivés de naphtalène et de l'indane, médicaments contenant ces composés et leurs procédés de préparation - Google Patents

Dérivés de naphtalène et de l'indane, médicaments contenant ces composés et leurs procédés de préparation Download PDF

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EP0259782B1
EP0259782B1 EP87112865A EP87112865A EP0259782B1 EP 0259782 B1 EP0259782 B1 EP 0259782B1 EP 87112865 A EP87112865 A EP 87112865A EP 87112865 A EP87112865 A EP 87112865A EP 0259782 B1 EP0259782 B1 EP 0259782B1
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group
propyl
dimethoxy
ethyl
formula
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English (en)
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EP0259782A1 (fr
Inventor
Manfred Dr. Dipl.-Chem. Psiorz
Joachim Dr. Dipl.-Chem. Heider
Andreas Dr. Dipl.-Chem. Bomhard
Norbert Dr. Dipl.-Chem. Hauel
Klaus Dr. Dipl.-Chem. Noll
Berthold Dr. Dipl.-Chem. Narr
Christian Dr. Lillie
Walter Prof Dr. Kobinger
Jürgen Dr. Dämmgen
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Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/417—Saturated compounds containing a keto group being part of a ring polycyclic
    • C07C49/423—Saturated compounds containing a keto group being part of a ring polycyclic a keto group being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5304—Acyclic saturated phosphine oxides or thioxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • EP-A-0.177.960 already describes tetrahydronaphthalenes which are substituted in the 2-position by a hydroxyl group which is optionally substituted by an acyl radical. These compounds have a pronounced calcium-antagonistic effect and can therefore be used as medicaments, in particular for the control or prevention of angina pectoris, ischemia, arrhythmias and high blood pressure.
  • the new naphthalene and indane derivatives of the formula their enantiomers have their diastereomers and acid addition salts thereof, particularly the physiologically acceptable acid addition salts with inorganic or organic acids, other valuable pharmacological properties, in particular a heart rate lowering effect, and a lowering effect on the 0 2 demand of the heart.
  • the present invention thus relates to the new tetrahydronaphthalene and indane derivatives of the formula I above, their enantiomers, their diastereomers, their acid addition salts, in particular for pharmaceutical use, their physiologically tolerable acid addition salts with inorganic or organic acids, processes for their preparation and medicaments containing these compounds .
  • n is the number 1 or 2
  • n is the number 1 or 2
  • A is a carbonyl group and R 7 is a hydrogen atom or
  • the new compounds are obtained by the following processes:
  • the reaction is advantageously carried out in a solvent or solvent mixture such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethyl sulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or in an excess of the compounds of the formulas II and / or III used and, if appropriate, in the presence of one Acid-binding agents, for example an alcoholate such as potassium tert-butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, the latter at the same time can serve as a solvent, or a reaction accelerator such as potassium iodide, depending on the reactivity of the nucleophil
  • the reaction is advantageously carried out in a solvent or solvent mixture such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethyl sulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or in an excess of the compounds of the formulas IV and / or V and, if appropriate, in the presence of a Acid-binding agents, for example an alcoholate such as potassium tert-butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, the latter at the same time can serve as a solvent, or a reaction accelerator such as potassium iodide, depending on the reactivity of the nucleophil
  • the reduction is preferably carried out with a metal hydride such as lithium aluminum hydride or diborane or with a complex of borane and a thioether, for example with borane-dimethyl sulfide complex, optionally in the presence of a Lewis acid such as boron trifluoride in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures between 0 and 80 ° C, but preferably at the boiling point of the solvent used, for example at temperatures between 35 and 65 ° C.
  • a metal hydride such as lithium aluminum hydride or diborane or with a complex of borane and a thioether, for example with borane-dimethyl sulfide complex
  • a Lewis acid such as boron trifluoride
  • suitable solvent such as diethyl ether or tetrahydrofuran
  • a 2 in a compound of formula VI used is a carbonyl group or R 8 is a hydroxyl group
  • the reduction is preferably carried out in the presence of a Lewis acid, for example with borane, for the preparation of compounds of formula I in which R 8 represents a hydrogen atom.
  • a Lewis acid for example with borane
  • a 2 in a compound of formula VI used is the carbonyl group or R B is a hydroxyl group
  • the reduction is preferably carried out with lithium aluminum hydride in order to prepare compounds of the general formula I in which R 8 is a hydroxyl group.
  • the oxidation is preferably carried out with an oxidizing agent such as potassium permanganate, barium manganate, potassium dichromate or with a ketone in the presence of a base (Oppenauer method), for example with acetone / aluminum isopropylate or benzophenone / potassium tert-butoxide, in a suitable solvent such as water, water / Dioxane, glacial acetic acid, water / acetic acid or toluene at temperatures between 0 and 150 ° C.
  • the oxidation with an inorganic oxidizing agent is preferably carried out at temperatures between 0 and 50 ° C. and the oxidation according to Oppenauer preferably at the boiling point of the reaction mixture, for example at temperatures between 50 and 115 ° C.
  • R 4 is an alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, bis (alkylsulfonyl) amino, N-alkylalkylsulfonylamino, alkylmercapto, alkoxy , Alkoxycarbonyloxy, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, phenylalkoxy, trifluoromethoxy, difluoromethoxy, cyanoalkoxy, alkylsulfonyloxy or trifluoromethylsulfonyloxy group:
  • R 10 represents an alkyl, alkanoyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulfonyl, phenylalkyl, trifluoromethyl, difluoromethyl or cyanoalkyl group, the alkyl and alkoxy parts mentioned above each having 1 to 3 carbon atoms or the alkanoyl part May contain 2 or 3 carbon atoms.
  • reaction is advantageously carried out in a solvent or solvent mixture such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally also in the presence of an acid-activating agent or a dehydrating agent, for.
  • a solvent or solvent mixture such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally also in the presence of an acid-activating agent or a dehydrating agent, for.
  • any reactive groups present such as hydroxyl, amino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • the trimethylsilyl, acetyl, benzoyl, benzoyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group
  • the protective radical for an imino or amino group is the acetyl, benzoyl, ethoxycarbonyl or benzyl group.
  • the optional subsequent removal of a protective radical used is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at the boiling point of the reaction mixture.
  • an aqueous solvent for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at the boiling point of the reaction mixture.
  • a benzyl radical is preferably split off hydrogenolytically, for example using hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C., but preferably at Room temperature, and a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon
  • a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid
  • an acid such as hydrochloric acid
  • the subsequent debenzylation is preferably carried out in a solvent such as water, water / ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium / carbon at temperatures between 0 and 50 ° C., preferably however carried out at room temperature.
  • a hydrogenation catalyst such as Raney nickel, platinum or palladium / carbon at temperatures between 0 and 50 ° C., preferably however carried out at room temperature.
  • the compounds of formula I obtained can be separated into their diastereomers, for example by column chromatography, and into their enantiomers, for example by column chromatography on a chiral phase or by crystallization with optically active acids, e.g. with D- or L-monomethyltartaric acid, D- or L-diacetyi tartaric acid, D- or L-tartaric acid, D- or L-lactic acid, D- or L-camphoric acid, D- or L-dibenzoyltartaric acid, D- or L-camphorsulfonic acid or D- or L-camphanic acid.
  • optically active acids e.g. with D- or L-monomethyltartaric acid, D- or L-diacetyi tartaric acid, D- or L-tartaric acid, D- or L-lactic acid, D- or L-camphoric acid, D- or L-dibenzoyltartaric acid, D- or L-camphors
  • the compounds of formula 1 obtained can also be converted into their acid addition salts, in particular for their pharmaceutical use, into their physiologically compatible acid addition salts with inorganic or organic acids.
  • suitable acids here are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid or oxalic acid.
  • a starting compound of the formula IV is obtained, for example, by reacting a carboxylic acid of the formula XI with a corresponding amine in the presence of N, N'-carbonyl-dilmidazole and then reducing the amide thus obtained.
  • a compound of the formulas VI, VII, VIII and X used as starting material is obtained by reacting a corresponding ⁇ -halogen compound with a corresponding amine.
  • the new compounds of the formula and their physiologically tolerable acid addition salts with inorganic or organic acids have valuable pharmacological properties, in particular in the case of minor central side effects, a particularly heart rate-lowering effect and a reduction in the 02 requirement of the heart.
  • the effect of the substances to be examined on the heart rate was examined per dose in 2 rats with an average weight of 250-300 g.
  • the rats were anesthetized with pentobarbital (50 mg / kg i.p. and 10 mg / kg s.c.).
  • pentobarbital 50 mg / kg i.p. and 10 mg / kg s.c.
  • the substances to be examined were injected into the jugular vein in aqueous solution (0.1 ml / 100 g).
  • the blood pressure was measured via a cannula embedded in a carotid artery and the heart rate was recorded from an EKG (11th or III. Lead) derived with needle electrodes.
  • the heart rate of the animals in the control period was between 350 and 400 beats / minutes (bpm).
  • the compounds produced according to the invention have no toxic side effects in therapeutic doses. For example, with intravenous application of substances A and C even in a high dose of 10 mg / kg to mice, apart from a small sedation, no toxic side effects were observed.
  • the compounds produced according to the invention are suitable for the treatment of sinus tachycardias of various origins and for the prophylaxis and therapy of ischemic heart diseases.
  • the dosage required to achieve a corresponding effect is expediently once or twice a day 0.03 to 0.4 mg / kg body weight, preferably 0.07 to 0.25 mg / kg body weight.
  • the active ingredient, corn starch, milk sugar and polyvinylpyrrolidone are mixed well and moistened with water.
  • the moist mass is pressed through a sieve with a 1 mm mesh size, dried at approx. 45 ° C and then the granules are passed through the same sieve.
  • domed dragee cores with a diameter of 6 mm are pressed on a tablet machine.
  • the dragee cores thus produced are coated in a known manner with a layer consisting essentially of sugar and talc.
  • the finished coated tablets are polished with wax. Drage weight: 130 mg
  • the active substance is dissolved in water for injection purposes in a suitable preparation vessel and the solution is made isotonic with sorbitol.
  • the solution After filtration through a membrane filter, the solution is poured into cleaned and sterilized ampoules with N 2 gassing and autoclaved in flowing steam for 20 minutes.
  • the hard fat is melted.
  • the ground active substance is homogeneously dispersed in the melt at 38 ° C. It is cooled to 35 ° C and poured into weakly pre-cooled suppository molds.
  • Dest. Water is heated to 70 ° C. Hydroxyethyl cellulose, benzoic acid and tartaric acid are dissolved therein with stirring. It is cooled to room temperature and the glycerin and the sorbitol solution are added with stirring. The active ingredient is added at room temperature and stirred until completely dissolved. Subsequently, the juice is evacuated with stirring.

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Claims (11)

1. Nouveaux dérivés de naphtalène et de l'indane de formule
Figure imgb0116
dans laquelle
n représente le nombre 1 ou 2,
A représente un groupe carbonyle et R7 un atome d'hydrogène ou
A représente un groupe de formule
Figure imgb0117
dans laquelle R8 représente un atome d'hydrogène, un groupe hydroxy, alcanoyloxy ou alcoxycarbonyloxy, et R7 représente un atome d'hydrogène ou R7 et R8 représentent ensemble une liaison supplémentaire,
E représente un groupe alcoylène avec 3 ou 4 atomes de carbone, rectiligne, éventuellement substitué par un groupe alcoyle,
G représente un groupe alcoylène avec 2 à 5 atomes de carbone, rectiligne, éventuellement substitué par un groupe alcoyle,
Ri représente un atome d'hydrogène ou d'halogène, un groupe trifluorométhyle, nitro, amino, alcoylamino, dialcoylamino, alcoyle, hydroxy, alcoxy ou phénylalcoxy, R2 représente un atome d'hydrogène ou un atome d'halogène, un groupe hydroxy, alcoxy, phénylalcoxy ou alcoyle, ou
R1 et R2 représentent ensemble un groupe alcoylènedioxy avec 1 ou 2 atomes de carbone,
Rs représente un atome d'hydrogène, un groupe alcoyle ou un groupe alcényle avec 3 à 5 atomes de carbone,
R4 représente un atome d'hydrogène ou d'halogène, un groupe alcoyle, amino, alcoylamino, dialcoylamino, alcanoylamino, alcoxycarbonylamino, alcoylsulfonylamino, bis(alcoylsulfonyl)amino, N-alcoyl-alcoylsulfonylamino, cyano, alcoylmercapto, alcoylsulfinyle ou alcoylsulfonyle, ou un groupe hydroxy éventuellement substitué par un groupe alcoyle, phénylalcoyle, 2-hydroxyéthyle, 3-hydroxy-n-propyle, 2-hydroxy-n-propyle, alcoylsulfonyle, cyanoalcoyle, alcoxycarbonyle, hydroxycarbonylalcoyle, alcoxycarbonylalcoyle, trifluorométhyle, difluorométhyle ou trifluorométhylsulfonyle,
R5 représente un atome d'hydrogène ou d'halogène, un groupe alcoyle, hydroxy, alcoxy, nitro, cyano ou trifluorométhyle, ou
R4 et Rs représentent ensemble un groupe alcoylènedioxy avec 1 ou 2 atomes de carbone et
R6 représente un atome d'hydrogène ou d'halogène, un groupe alcoyle ou alcoxy, tous les groupes alcoyle ou alcoxy mentionnés plus haut pouvant contenir chacun 1 à 3 atomes de carbone et les groupes alcanoyle mentionnés plus haut pouvant contenir chacun 2 ou 3 atomes de carbone, leurs énantiomères, leurs diastéréoisomères et leurs sels d'addition d'acides.
2. Nouveaux dérivés du naphtalène et de l'indane de formule 1 selon la revendication 1, dans laquelle
n représente le nombre 1 ou 2,
A représente un groupe carbonyle et R7 un atome d'hydrogène ou
A représente un groupe de formule
Figure imgb0118
dans laquelle R8 représente un atome d'hydrogène ou un groupe hydroxy, et
R7 représente un atome d'hydrogène ou R7 et Rs représentent ensemble une liaison supplémantaire,
E représente le groupe n-propylène,
G représente le groupe éthylène ou n-propylène,
R1 représente un groupe méthyle ou méthoxy,
R2 représente un atome d'hydrogène ou un groupe méthoxy,
Rs représente le groupe méthyle,
R4 représente un atome d'hydrogène, de chlore ou de brome, un groupe hydroxy, méthoxy, cyano, cya- nométhoxy, hydroxycarbonylméthoxy, méthoxycarbonylméthoxy, éthoxycarbonylméthoxy, méthyle, amino, acétylamino, méthoxycarbonylamino, méthylsulfonyloxy, trifluorométhylsulfonyloxy, benzyloxy, mé- thylsulfonylamino, ou bis(méthylsulfonylyamino,
R5 représente un atome d'hydrogène, de chlore ou de brome, un groupe méthoxy ou nitro et
R6 représente un atome d'hydrogène, de chlore ou de brome, leurs énantiomères, leurs diastéréoisomères et leurs sels d'addition d'acides.
3. Nouveaux dérivés de naphtalène et de l'indane de formule I selon la revendication 1, dans laquelle R1 à Rs, A, E, G et n sont définis comme dans la revendication 2,
R4 représente un groupe méthoxy,
R5 représente un groupe méthoxy, et
Re représente un atome d'hydrogène, leurs énantiomères, leurs diastéréoisomères et leurs sels d'addition d'acides.
4. Le 6,7-diméthoxy-2-[3-((2-(3,4-diméthoxyphényl)-éthyl)-méthylamino)-propyl]-1-oxo-1,2,3,4-tétra- hydronaphtalène et ses sels d'addition d'acides.
5. Le 6,7-diméthoxy-2-[3-((2-(3,4-diméthoxyphényl)-éthyl)-méthylamino)-propyl]-1,2,3,4-tétrahydro- naphtalène et ses sels d'addition d'acides.
6. Sels d'addition d'acides physiologiquement supportables des composés selon les revendications 1, à 5 avec des acides non organiques ou organiques.
7. Médicament contenant un composé de fomrule générale I selon les revendicaitons 1 à 5 ou son sel d'addition d'acide physiologiquement supportable selon la revendication 6, conjointement à un ou plusieurs excipients et/ou diluants inertes.
8. Médicament selon la revendication 7 convenant au traitement des tachycardies sinusales et des maladies cardiaques ischémiques.
9. Procédé pour la fabrication d'un médicament selon les revendications 7 et 8, caractérisé en ce que, par voie non chimique, on introduit un composé selon les revendications 1 à 5 ou son sel d'addition d'acide physiologiquement supportable selon la revendication 6, dans un ou plusieurs excipients et/ou diluants inertes.
10. Procédé pour la fabrication des nouveaux dérivés de naphtalène et de l'indane selon les revendications 1 à 6, caractérisé en ce que
a) pour la fabrication des composés de formule I dans laquelle R7 et R8 représentent chacun un atome d'hydrogène ou représentent ensemble une liaison supplémentaire, on fait réagir un composé de formule
Figure imgb0119
dans laquelle
Ri, R2, n et E sont définis comme dans les revendications 1 à 5,
Ai représente un groupe de formule
Figure imgb0120
dans laquelle
R8 représente un atome d'hydrogène, et R7 représente un atome d'hydrogène ou R7 et R8 représentent ensemble une liaison supplémentaire, et
X représente un groupe partant nucléophile tel qu'un atome d'halogène ou un groupe sulfonyloxy, avec une amine de formule
Figure imgb0121
dans laquelle
R3 à R6 et G sont définis comme dans les revendications 1 à 5 ou
b) on fait réagir un composé de formule
Figure imgb0122
dans laquelle
n, A, E, R1 à R3 et R7 sont définis comme dans les revendications 1 à 5, avec un composé de formule
Figure imgb0123
dans laquelle
R4 à R6 et G sont définis comme dans les revendications 1 à 5 et Y représente un groupe partant nucléophile tel qu'un atome d'halogène ou un groupe sulfonyloxy ou
c) pour la fabrication des composés de formule I dans laquelle A représente un groupe de formule
Figure imgb0124
dans laquelle R8 représente un atome d'hydrogène ou un groupe hydroxy, on réduit un composé de formule
Figure imgb0125
dans laquelle
n et R1 à R6 sont définis comme dans les revendications 1 à 5,
A2 représente un groupe carbonyle et R7 un atome d'hydrogène ou
A2 représente un groupe de formule
Figure imgb0126
dans
R8 représente un atome d'hydrogène ou groupe hydroxy, et
R7 représente un atome d'hydrogène,
E' possède les significations mentionnées dans les revendications 1 à 5 pour E ou G' possède les significations mentionnées dans les revendications 1 à 5 pour G, toutefois dans les radicaux E ou G un groupe méthylène voisin du groupe N-Rs devant être remplacé par un groupe carbonyle ou
d) pour la fabrication des composés de formule I dans laquelle A représente le groupe carbonyle, on oxyde un composé de formule
Figure imgb0127
dans laquelle
n, E, G et R1 à R6 sont définis comme dans les revendications 1 à 5 ou
e) pour la fabrication des composés de formule I dans laquelle R4 représente un groupe alcoylamino, dialcoylamino, alcanoylamino, alcoxycarbonylamino, alcoylsulfonylamino, bis(alcoylsulfonyl)amino, N-alcoyl- alcoylsulfonylamino, alcoylmercapto, alcoxy, alcoxycarbonyloxy, hydroxycarbonylalcoxy, alcoxycarbo- nylalcoxy, phénylalcoxy, trifluorométhoxy, difluorométhoxy, cyanoalcoxy, alcoylsulfonyloxy ou trifluorométhylsulfonyloxy, on fait réagir un composé de formule
Figure imgb0128
dans laquelle
R1 à Rs, Rs à R7, A, E, G et n sont définis comme dans les revendications 1 à 5, et
R9 représente un groupe hydroxy, amino ou alcoylamino avec 1 à 3 atomes de carbone, avec un composé de formule Z - R>! )(IX) dans laquelle
Z représente un groupe partant nucléophile tel qu'un atome d'halogène et
Rio représente un groupe alcoyle, alcanoyle, alcoxycarbonyle, hydroxycarbonylalcoyle, alcoxycarbonylalcoyle, alcoylsulfonyle, phénylalcoyle, trifluorométhyle, difluorométhyle ou cyanoalcoyle, les parties alcoyle et alcoxy mentionnées plus haut pouvant contenir chacune 1 à 3 atomes de carbone ou respectivement la partie alcanoyle 2 à 3 atomes de carbone ou
g) pour la fabrication des composés de formule I dans laquelle R7 et R8 représentent ensemble une liaison supplémentaire, on déshydrate un composé de formule
Figure imgb0129
dans laquelle
n, E, G et R1 à R7 sont définis comme dans les revendications 1 à 5,
si nécessaire un groupe protecteur utilisé pour la protection des groupes réactifs dans les réactions a)
EP87112865A 1986-09-11 1987-09-03 Dérivés de naphtalène et de l'indane, médicaments contenant ces composés et leurs procédés de préparation Expired - Lifetime EP0259782B1 (fr)

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AT87112865T ATE59378T1 (de) 1986-09-11 1987-09-03 Neue naphtalin- und indanderivate, diese verbindungen enthaltende arzneimittel und verfahren zu deren herstellung.

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DE19863630903 DE3630903A1 (de) 1986-09-11 1986-09-11 Neue tetrahydronaphthalin- und indanderivate, verfahren zu deren herstellung sowie diese enthaltende arzneimittel
DE3630903 1986-09-11

Publications (2)

Publication Number Publication Date
EP0259782A1 EP0259782A1 (fr) 1988-03-16
EP0259782B1 true EP0259782B1 (fr) 1990-12-27

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EP87112865A Expired - Lifetime EP0259782B1 (fr) 1986-09-11 1987-09-03 Dérivés de naphtalène et de l'indane, médicaments contenant ces composés et leurs procédés de préparation

Country Status (16)

Country Link
EP (1) EP0259782B1 (fr)
JP (1) JPS6377842A (fr)
KR (1) KR880003889A (fr)
AT (1) ATE59378T1 (fr)
AU (1) AU597719B2 (fr)
DD (1) DD263525A5 (fr)
DE (2) DE3630903A1 (fr)
DK (1) DK472387A (fr)
FI (1) FI873917A (fr)
HU (1) HU206077B (fr)
IL (1) IL83850A (fr)
NO (1) NO166528C (fr)
NZ (1) NZ221766A (fr)
PH (1) PH25680A (fr)
PT (1) PT85689B (fr)
ZA (1) ZA876768B (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0338793A2 (fr) * 1988-04-20 1989-10-25 The Wellcome Foundation Limited Sulfonanilides antihypertensifs
EP0361577A1 (fr) * 1988-09-19 1990-04-04 Akzo N.V. Dérivés de tétrahydronaphthalène et indane
US5166209A (en) * 1989-04-21 1992-11-24 Burroughs Wellcome Co. Pharmacologically active compounds
US5180746A (en) * 1989-02-17 1993-01-19 Takeda Chemical Industries, Ltd. Aralkylamine compounds
WO1995007075A1 (fr) * 1993-09-09 1995-03-16 Synaptic Pharmaceutical Corporation Nouveaux derives d'amine aromatique
US5643784A (en) * 1990-12-04 1997-07-01 H, Lundbeck A/S Indan derivatives
US5658921A (en) * 1992-06-12 1997-08-19 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US5807871A (en) * 1991-06-13 1998-09-15 H. Lundbeck A/S Piperidine derivatives having anxiolytic effect
US6048877A (en) * 1997-02-21 2000-04-11 Bristol-Myers Squibb Company Tetralone derivatives as antiarrhythmic agents

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9103745D0 (sv) * 1991-12-18 1991-12-18 Wikstroem Haakan Aryl-triflates and related compounds
JPH09502193A (ja) * 1993-09-09 1997-03-04 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー 抗高血糖症および／または抗肥満症活性を有するホスフィン酸誘導体
CA2276278C (fr) 1997-02-27 2009-04-07 Takeda Chemical Industries, Ltd. Composes du type amine, et methode de production et utilisation connexes
AU2001244700A1 (en) 2000-04-03 2001-10-15 Takeda Chemical Industries Ltd. Process for producing amine derivatives

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CS159795B2 (fr) * 1971-04-19 1975-01-31
CH654294A5 (it) * 1982-07-09 1986-02-14 Yason Srl Composti ad attivita bloccante del calcio a livello cardiaco e cerebrale, metodo per la loro preparazione e composizioni farmaceutiche.
NZ213651A (en) * 1984-10-11 1989-07-27 Hoffmann La Roche Tetrahydronapthalene derivatives and medicaments
DK691488A (da) * 1987-12-14 1989-06-15 Beecham Group Plc Hidtil ukendte forbindelser

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0338793A2 (fr) * 1988-04-20 1989-10-25 The Wellcome Foundation Limited Sulfonanilides antihypertensifs
EP0338793A3 (fr) * 1988-04-20 1991-01-02 The Wellcome Foundation Limited Sulfonanilides antihypertensifs
EP0361577A1 (fr) * 1988-09-19 1990-04-04 Akzo N.V. Dérivés de tétrahydronaphthalène et indane
US4980354A (en) * 1988-09-19 1990-12-25 Akzo N.V. Tetrahydronaphthalene and indane derivatives
US5180746A (en) * 1989-02-17 1993-01-19 Takeda Chemical Industries, Ltd. Aralkylamine compounds
US5166209A (en) * 1989-04-21 1992-11-24 Burroughs Wellcome Co. Pharmacologically active compounds
US5643784A (en) * 1990-12-04 1997-07-01 H, Lundbeck A/S Indan derivatives
US5807871A (en) * 1991-06-13 1998-09-15 H. Lundbeck A/S Piperidine derivatives having anxiolytic effect
US6031099A (en) * 1991-06-13 2000-02-29 H. Lundbeck A/S Piperidine derivates having anxiolytic effect
US6207677B1 (en) 1991-06-13 2001-03-27 H. Lundbeck A/S Piperidine derivatives having anxiolytic effect
US5658921A (en) * 1992-06-12 1997-08-19 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US5684012A (en) * 1992-06-12 1997-11-04 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US5830896A (en) * 1992-06-12 1998-11-03 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US5837707A (en) * 1992-06-12 1998-11-17 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US6090808A (en) * 1992-06-12 2000-07-18 H. Lundbeck A/S Dimeric piperidine, tetrahydropyridine and piperazine derivatives
US5508306A (en) * 1992-11-13 1996-04-16 Synaptic Pharmaceutical Corporation Aromatic amine derivatives
WO1995007075A1 (fr) * 1993-09-09 1995-03-16 Synaptic Pharmaceutical Corporation Nouveaux derives d'amine aromatique
US6048877A (en) * 1997-02-21 2000-04-11 Bristol-Myers Squibb Company Tetralone derivatives as antiarrhythmic agents

Also Published As

Publication number Publication date
PH25680A (en) 1991-09-04
HU206077B (en) 1992-08-28
DE3767094D1 (de) 1991-02-07
NO166528B (no) 1991-04-29
NO166528C (no) 1991-08-07
EP0259782A1 (fr) 1988-03-16
DK472387A (da) 1988-03-12
PT85689B (pt) 1990-06-29
PT85689A (de) 1987-10-01
KR880003889A (ko) 1988-05-30
AU7829787A (en) 1988-03-17
DK472387D0 (da) 1987-09-10
IL83850A (en) 1991-09-16
DE3630903A1 (de) 1988-03-24
JPS6377842A (ja) 1988-04-08
FI873917A (fi) 1988-03-12
HUT46885A (en) 1988-12-28
AU597719B2 (en) 1990-06-07
ZA876768B (en) 1989-05-30
DD263525A5 (de) 1989-01-04
NO873784D0 (no) 1987-09-10
FI873917A0 (fi) 1987-09-10
NZ221766A (en) 1989-05-29
NO873784L (no) 1988-03-14
ATE59378T1 (de) 1991-01-15
IL83850A0 (en) 1988-02-29

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